Stress-induced pulse pressure change predicts women's carotid atherosclerosis

BACKGROUND AND PURPOSE: Individuals who exhibit large increases in blood pressure and heart rate during mental stress may be at risk for accelerated atherosclerosis. This report evaluates the association between stress-induced hemodynamic responses and carotid atherosclerosis in 254 healthy postmenopausal women. METHODS: The magnitude of change in blood pressure and heart rate from rest to public speaking and mirror image tracing, two stressful tasks, was measured. Average intima-media thickness (IMT) and focal plaque in the common carotid artery, bulb, and internal carotid artery were measured with the use of duplex ultrasonography on average 2.3 years later. RESULTS: The average IMT was 0.77 mm, with a range of 0.60 to 1.37; 52.5% had at least one plaque. Correlational analysis showed that greater IMT was associated with greater pulse pressure change during mental stress (r = 0.17, P < 0.01). Statistical adjustments for possible confounders (age, hormone replacement therapy use, resting pulse pressure, smoking status, and triglyceride levels) did not alter the results. The plaque index was associated with greater pulse pressure change during the mirror image tracing task (odds ratio = 1.47, P = 0.01) for women with a plaque score of > or = 2 versus 1 or 0, adjusted for possible confounders. CONCLUSIONS: Mental stress-induced pulse pressure changes may influence the development of early atherosclerosis in the carotid artery of women. Widening of pulse pressure during stress, as well as at rest, may be a marker of compromised compliance in the vessel wall.     

Association of hormone replacement therapy and carotid wall thickness in women with and without diabetes

OBJECTIVE: Atherosclerosis is the major underlying cause of death for women with type 2 diabetes. We examined the relationship between use of postmenopausal hormone replacement therapy(HRT) and subclinical atherosclerosis among women with type 2 diabetes, impaired glucose tolerance (IGT), and normal glucose tolerance. RESEARCH DESIGN AND METHODS: A cross-sectional analysis was conducted among 623 postmenopausal women in the Insulin Resistance Atherosclerosis Study (IRAS). Current users of HRT, n = 200, were compared with 104 former users and 319 never users. Intimal-medial wall thicknesses (IMTs) of the common carotid (CCA) and internal carotid (ICA) arteries were used as measures of atherosclerosis. RESULTS: Significant differences between HRT user groups were noted for certain demographic, socioeconomic, and lifestyle factors. After adjustment for these and other coronary heart disease risk factors, current users had a 69 microm thinner ICA IMT than never users (P = 0.06). Former users had a 96 pm thinner ICA IMT than never users (P = 0.03). No significant difference was observed for the CCA. Although women with type 2 diabetes had thicker carotid IMT than women without diabetes, the association between HRT use and thinner IMT was similar in both groups. The difference between current and never users was attenuated by adjustment for HDL and LDL cholesterol. Neither duration of HRT use nor HRT regimen was associated with IMT in either artery. CONCLUSIONS: This analysis suggests that current and former use of HRT is associated with reduced atherosclerosis and that women with type 2 diabetes may receive the same benefit from HRI as women without diabetes.     

Decrease in glomerular filtration rate in Japanese patients with type 2 diabetes is linked to atherosclerosis

OBJECTIVE: We assessed the effects of atherosclerosis on the glomerular filtration rate (GFR) in patients with type 2 diabetes and who had micro- or normoalbuminuria. RESEARCH DESIGN AND METHODS: A total of 61 Japanese patients with type 2 diabetes were recruited from inpatients of Osaka City University Hospital. They ranged in age from 40 to 69 years (28 men and 33 women). Each subject collected a 24-h urine sample for quantitative analysis of albumin. Absence of albuminuria was defined as a urinary albumin excretion level of <30 mg/24 h (n = 36) and microalbuminuria as a level of 30-300 mg/24 h. The GFR was estimated using 99mTc diethylenetriamine pentaacetic renogram method. As indexes of atherosclerosis, we measured the intimal-medial thickness (IMT) and distensibility of the carotid artery using high-resolution B-mode ultrasonagraphy and an echo-tracking system. We measured the resistance index (RI) of the renal interlobar arteries by pulsed Doppler sonography. RESULTS: The clinical characteristics of type 2 diabetic patients with and without microalbuminuria did not differ except for duration of diabetes, which was longer in the patients with microalbuminuria. GFR also did not differ between the patients with and without microalbuminuria. GFR was significantly correlated with the patient's age (r = -0.256, P < 0.05), carotid IMT (r = -0.326, P < 0.05), carotid stiffness beta (r = -0.449, P < 0.001), and renal arterial RI (r = -0.365, P < 0.05). In multiple regression analysis, independent factors associated with GFR were carotid IMT (R2 = 0.108, P = 0.0102), carotid stiffness beta (R2 = 0.208, P = 0.0003), and renal artery RI (R2 = 0.130, P = 0.0043). CONCLUSIONS: The decline in GFR in type 2 diabetic patients in the early stages of nephropathy may be due in part to atherosclerosis.     

Ultrasonographically assessed maximum carotid artery wall thickness in Mexico City residents and Mexican Americans living in San Antonio, Texas. Association with diabetes and cardiovascular risk factors

Measurements of carotid artery wall thickness are often used as a surrogate for atherosclerosis. However, few studies have performed these measurements in populations of Mexican origin. Since Mexicans in Mexico City consume high-carbohydrate diets and have carbohydrate-induced dyslipidemia (high triglyceride and low HDL cholesterol levels) compared with Mexican Americans living in San Antonio, Tex, we questioned whether they also had more atherosclerosis than San Antonio Mexican Americans. Mean maximum intimal-medial thickness (IMT) of the common (CCA) and internal (ICA) carotid arteries were measured in 867 subjects aged 35 to 64 years (40% men) in two Mexican-origin populations, one from San Antonio (n = 202) and the other from Mexico City (n = 665). IMT's in the two cities were compared, and their associations with cardiovascular risk factors were analyzed. Older age, male sex, high levels of total cholesterol, low levels of HDL cholesterol, and high systolic blood pressure were positively associated with both CCA IMT and ICA IMT. Cigarette smoking was significantly associated with ICA IMT. CCA and ICA IMTs in diabetic subjects were thicker than in nondiabetic subjects in both men and women (all P < = .05). CCA IMT was thicker in the San Antonio than the Mexico City subjects after adjustment for cardiovascular risk factors (0.81 versus 0.76 mm in men and 0.77 versus 0.71 mm in women; P < .001 for city difference). San Antonio men also had thicker ICA IMT than their counterparts in Mexico City (0.88 versus 0.83 mm), but the reverse was true for women (0.73 versus 0.77 mm; interaction between sex and city, P < .05). Our results indicate that men had higher carotid IMTs than women. CCA IMT was thicker in San Antonio Mexican Americans than in Mexico City residents. The differences in ICA IMTs between San Antonio and Mexico City were inconsistent. Thus, since Mexico City residents consume high-carbohydrate diets, the data do not support an atherogenic effect of such diets. The interaction between sex and city on ICA IMT deserves further study.     

Relationships of cerebral MRI findings to ultrasonographic carotid atherosclerosis in older adults : the Cardiovascular Health Study. CHS Collaborative Research Group

Cerebral magnetic resonance imaging (MRI) has demonstrated a high prevalence of infarct-like lesions, white matter hyperintensities, and evidence of cerebral atrophy in older adults. While these findings are generally believed to be related to ischemia and atherosclerosis, their relationship to atherosclerosis in the carotid arteries remains to be explored. Study subjects were part of the multicenter Cardiovascular Health Study, a cross-sectional study of 3502 women and men >/=65 years of age undergoing cranial MRI and carotid ultrasonography. MRI infarcts were detected in 1068 participants (29.3%) and measurable carotid plaque in 2745 (75.3%). MRI infarcts, ventricular and sulcal widening, and white matter score were strongly associated with carotid intimal-medial thickness (IMT) and stenosis degree after adjustment for age and sex (all P<0. 01). Associations with plaque characteristics were less strong and less consistent; MRI infarcts were weakly associated only with surface irregularity, and ventricular size was weakly associated only with lesion density (both P<0.04). In contrast, sulcal widening was strongly related to plaque characteristics, with scores being higher in those with heterogeneous and irregular plaque (both P<0. 009). Adjustment for other risk factors, and for carotid IMT/stenosis, removed associations of MRI findings with plaque characteristics except for weak relationships remaining between MRI infarcts and surface irregularity and between sulcal score and heterogeneous plaque (both P<0.03). MRI abnormalities show strong and consistent relationships with increasing carotid IMT and stenosis degree but less strong associations with plaque characteristics, especially after adjusting for IMT and stenosis.     

Cardiovascular risk factors for early carotid atherosclerosis in the general population: the Edinburgh Artery Study

BACKGROUND: Recent attempts to identify cardiovascular risk factors affecting early-stage carotid atherosclerosis, measured by ultrasonographically assessed intima-media thickness, have been inconclusive. OBJECTIVE: To study the relationship between traditional cardiovascular risk factors and intima-media thickness. METHODS: Ultrasonic evaluation of the intima-media thickness of the common carotid artery was included in the 5-year follow-up examination of participants of the Edinburgh Artery Study. We had valid readings of intima-media thickness for 1106 men and women aged 60-80 years. Information on a range of cardiovascular risk factors had been collected during the baseline examination. RESULTS: For men, in addition to age, lifetime smoking (measured in terms of pack years) was the only cardiovascular risk factor associated with increased intima-media thickness (P< or = 0.01) in the univariate analysis. Both systolic blood pressure (P < or = 0.001) and the high-density lipoprotein (HDL: total cholesterol ratio (P < or = 0.01) were correlated with intima-media thickness for women. When all the variables had been included in a multivariate analysis, pack years of smoking and the HDL:total cholesterol ratio were associated with early atherosclerotic development in men. In an equivalent analysis for women, alcohol consumption, systolic blood pressure and the HDL:total cholesterol ratio were associated with intima-media thickness. CONCLUSION: These data suggest that risk factors affecting intima-media thickness differ for men and women. Further sex-specific analyses of prospective population studies are required in order to clarify the role of 'traditional' cardiovascular risk factors in the early stages of carotid atherosclerosis.     

Thalamic NMDA transmission in a genetic model of absence epilepsy in rats

OBJECTIVES: Whether menopause per se influences fat distribution independently of the effect of aging remains controversial. The lack of consistency in the menopause related changes in body fat distribution may be the result of differences in the methods for measuring fat distribution or in the characteristics of the women studied. The aim of this cross sectional study in obese women was to compare total body composition and regional fat and lean distribution, in premenopausal, perimenopausal and postmenopausal women. METHODS: Body composition was assessed by dual energy X-ray absorptiometry (DEXA) in premenopausal (n = 26), perimenopausal (n = 24) and postmenopausal (n = 73) obese women with no intercurrent diseases. RESULTS: It was shown that postmenopausal obese (n = 73) women had a higher proportion of total fat mass in the trunk and a lower proportion of total fat and lean mass in the femoral and leg regions than premenopausal women after adjustment for age and total fat mass. In the same analysis, perimenopausal women had a lower proportion of total fat in the leg and femoral regions and of total lean in the femoral region than premenopausal women; they had a regional body composition similar to that of postmenopausal women. CONCLUSION: The present data indicate that in obese women, post menopause and perimenopause are associated with differences in fat and lean distribution, independently of age and total fat.     

Age-related deterioration in arterial structure and function in postmenopausal women: impact of hormone replacement therapy

Epidemiological evidence suggests that hormone replacement therapy (HRT) reduces morbidity and mortality from cardiovascular diseases in postmenopausal women. In this study, indices of arterial function [total systemic arterial compliance (SAC) and carotid arterial distensibility coefficient (DC)], structure [carotid intima-media thickness (IMT)], and lipid profiles were compared in postmenopausal women on long-term HRT and aged-matched controls. One hundred nine women aged 44 to 77 years taking HRT and an age-matched group of 108 female controls were entered into the study. The two groups were similar for body mass index, smoking status, exercise level, alcohol intake, and blood pressure. Fasting cholesterol, low density lipoprotein, and lipoprotein(a) were reduced and high density lipoprotein increased in the HRT group. IMT increased with age; SAC and DC were reduced with age in both groups. The HRT group had a higher mean SAC (0.42+/-0.02 versus 0.34+/-0.02 U/mm Hg, P=0.0001) and a lower mean IMT (0.67+/-0.01 versus 0.74+/-0.02 mm, P=0.006) than did controls. Subgroup analysis for estrogen versus estrogen plus progestin revealed no differences for SAC and IMT; DC, however, was greater in estrogen-only users. Smokers on HRT had a higher mean SAC (0.41+/-0.02 versus 0.31+/-0.01 U/mm Hg, P=0.008) and a lower IMT (0.65+/-0.02 versus 0.75+/-0.03 mm, P=0.002) than did smokers not taking such therapy. A protective effect of long-term estrogen therapy on age-related changes in arterial structure and function in postmenopausal women was evident in smokers and nonsmokers alike. Progestin appeared to counteract the effects of estrogen on carotid compliance only. Long-term controlled trials are needed to determine the significance of these findings.     

Modulation of circulating cellular adhesion molecules in postmenopausal women with coronary artery disease

OBJECTIVES: The present study examined the association of estrogen (E2) and the inflammatory response of endothelium in coronary artery disease (CAD) by measuring circulating cellular adhesion molecules (cCAMs) in subjects with atherosclerosis. BACKGROUND: Atherosclerotic plaque demonstrates features similar to inflammation. Endothelial cell activation by inflammatory cytokines induces expression of cellular adhesion molecules (CAMs), thereby perhaps augmenting leukocyte adhesion and recruitment and subsequent development of atherosclerosis. The incidence of CAD is lower in women; this may be due to the cardioprotective effects of E2. METHODS: Consecutive eligible subjects with CAD admitted for cardiac catheterization were studied. The groups evaluated were men, postmenopausal women receiving E2 replacement therapy (ERT), postmenopausal women not receiving ERT and premenopausal women. Control groups included men and women without CAD. Preprocedural blood samples were drawn from all groups. Measurements of cCAMs, E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 were performed by enzyme-linked immunoabsorbant assay. E2 levels were assessed by radioimmunoassay. RESULTS: We observed a statistically significant increase in all cCAMs in men with CAD and postmenopausal women with CAD not receiving ERT compared with postmenopausal women with CAD receiving ERT. Premenopausal women with CAD and postmenopausal women with CAD receiving ERT had a significant increase in VCAM-1 alone compared with the female control group. CONCLUSIONS: A possible mechanism by which E2 exerts one of its cardioprotective effects is by limiting the inflammatory response to injury by modulating the expression of CAMs from the endothelium.     

Ultrasound velocity of the tibia in normal German women and hip fracture patients

One of the latest developments in quantitative ultrasound (QUS) is the measurement of the speed of sound (SOS) of cortical bone of the midtibia. To determine the diagnostic validity of this method we measured 150 healthy women aged 22-94 years. Additionally, we report on first results of patients with hip fracture. Precision in vivo of the tibial QUS expressed as the percentage coefficient of variation (CV) was 0.39% for the first day and 0.45% after repositioning the second day (mean CV = 0.42%). No significant dependency of tibial SOS was found with weight, height, and body mass index in pre- and postmenopausal women. There was a significant decline of SOS with age in postmenopausal women (SOS = 4225 - 5.3 age, r = -0.46, P < 0. 001), whereas premenopausal women showed no decline (SOS = 3906 + 1. 3 age, r = 0.13, ns) Mean SOS values of premenopausal women were significantly higher than those of postmenopausal women (3960 +/- 78.7 m/second and 3898 +/- 120 m/second, respectively, P < 0.001). Postmenopausal women on estrogen substitution had significantly higher mean tibial SOS values than age-comparable postmenopausal women without estrogen substitution (3980 +/- 99 m/second and 3869 +/- 100 m/second, respectively, P < 0.001). Significant difference between age-matched healthy women, n = 11, and hip fracture patients, n = 13, expressed as z-score of -1.4 SD was found. In conclusion, tibial QUS declines with age and detects higher values in premenopausal women and postmenopausal women on estrogen substitution and lower values in hip fracture patients. Further prospective studies are needed to clarify its role in fracture risk assessment.     

Carotid atherosclerosis in adolescents and young adults with IDDM. Relation to urinary endothelin, albumin, free cortisol, and other factors

OBJECTIVE: To investigate 1) alterations of carotid intimal-plus-medial thickness (IMT) in subjects with IDDM and 2) the relation of IMT to indexes of diabetic angiopathy and to risk factors of atherosclerosis. RESEARCH DESIGN AND METHODS: IMT was assessed by ultrasound B-mode imaging in 39 subjects with IDDM (23 male, 16 female young adults aged 17.5 +/- 5.2 years, diabetes duration 8.8 +/- 5.9) and in 22 control subjects (healthy siblings of the IDDM subjects) of comparable age. Urinary endothelin (UET1) and urinary free cortisol (UFC) were determined by radioammunoassay (RIA), urinary albumin by nephelometry, HbA1c by high-performance liquid chromatography (HPLC), and plasma renin by immunoradiometric assay (IRMA). RESULTS: The IMT values were greater in IDDM subjects than in control subjects (0.49 +/- 0.1 mm, 0.44 +/- 0.09 mm, respectively; P = 0.048) and greater in IDDM male subjects than in control male subjects (0.52 +/- 0.09 and 0.44 +/- 0.06 mm, respectively; P = 0.015), with no difference between IDDM and control female subjects. The IMT values were greater in diabetic male subjects than in female subjects (0.52 +/- 0.09 and 0.45 +/- 0.1 mm, respectively; P = 0.017). In IDDM subjects, but not in control subjects, there was a positive correlation of IMT to urinary albumin (P = 0.008), systolic blood pressure (P = 0.023), UET1 (P = 0.016), UFC (P = 0.002), and BMI (P = 0.021). Multiple regression analysis demonstrated that in IDDM subjects the variable that interacts independently with IMT was the BMI (P = 0.001). CONCLUSIONS: IMT, an index of atherosclerosis (macroangiopathy), is increased in IDDM subjects quite early (already in adolescence), and it is positively related to urinary albumin, UET1, blood pressure, and UFC.     

Chronic stress burden, discrimination, and subclinical carotid artery disease in African American and Caucasian women.

This study examined the association between a composite index of stress that included measures of life events, ongoing stress, discrimination, and economic hardship and subclinical carotid disease among 109 African American and 225 Caucasian premenopausal women. African Americans reported more chronic stress and had higher carotid intima-media thickness (IMT) as compared with Caucasians. Among African Americans only, the composite stress index and unfair treatment were associated with higher IMT. These effects were partially mediated by biological risk factors. African Americans who reported experiencing racial discrimination had marginally more carotid plaque than did those who did not report experiencing racial discrimination. The results suggest that African Americans may be particularly vulnerable to the burden of chronic stress. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gender differences in intima-media permeability to low-density lipoprotein at atherosclerosis-prone aortic sites in rabbits. Lack of effect of 17 beta-estradiol

Premenopausal women are protected from coronary heart disease, and premenopausal nonhuman primates are protected from atherosclerosis, the underlying cause of coronary heart disease. Estrogen is thought to account for this protection in females, and part of this protection is independent of the effects on risk factors, including lipoprotein levels. This study considered the hypothesis that reduced intima-media permeability to low-density lipoproteins (LDL) may account for the protection from atherosclerosis and coronary heart disease in premenopausal females and that this effect might be mediated by estrogen. Intima-media permeability to LDL was determined in male and female rabbits made hypercholesterolemic by feeding them 0.5% cholesterol for 8 days. The diet of half of the female rabbits was supplemented with 17 beta-estradiol (4 mg/d) during cholesterol feeding and the preceding 4 weeks. Estrogen treatment in the female rabbits did not influence the intima-media permeability to LDL. However, intima-media permeability to LDL for branch sites of the abdominal aorta and aortic arch (regions highly susceptible to atherosclerosis) was 43% and 38% lower, respectively, in male rabbits than in female rabbits: (2.93 +/- 0.39 microL/h/g, (n = 8), vs 6.28 +/- 0.86 microL/h/g, (n = 16), P < .001, and 4.69 +/- 0.28 microL/h/g, (n = 8) vs 7.57 +/- 0.75 microL/h/g, (n = 16), P < .02). In contrast, intima-media permeability to LDL in 7 of 8 aortic sites relatively resistant to atherosclerosis did not differ between male and female rabbits. These data suggest that the protection from atherosclerosis associated with female sex and estrogen is mediated by mechanism(s) other than reduction in intima-media permeability to LDL.     

Peripheral monocyte culture supernatants of menopausal women can induce bone resorption: involvement of cytokines

Increased bone resorption is a mechanism contributing to bone loss in the postmenopausal period. Cytokines are involved in osteoclastic differentiation and, therefore, may play a role in the regulation of bone resorption. Several previous works showed the implication of interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF alpha) in the modulation of bone remodeling. This study determines the concomitant production of the three cytokines and tests the bone-resorbing activity of peripheral monocyte supernatants. Four groups of women were studied: premenopausal women (n = 13; mean age, 47 +/- 0.9 yr), untreated postmenopausal women (n = 21; mean age, 52 +/- 0.6 yr), postmenopausal women treated with estrogens (n = 14; mean age, 54.2 +/- 1.1 yr), or postmenopausal women treated with ethanehydroxydiphosphonate (n = 12; mean age, 53.2 +/- 2 yr). Assignment to clinical groups was verified by plasma FSH and estradiol determinations. Lumbar spine bone mineral density was significantly higher in the premenopausal women group than in the three postmenopausal groups. Peripheral blood monocytes were cultured for 48 h with 20% autologous plasma, and after stimulation with lipopolysaccharides. IL-1, IL-6, and TNF alpha levels were measured by RIA in the monocyte surpernatants. The three cytokines were highly correlated to each other, IL-1 with IL-6 (r = 0.76; P < 0.001), IL-1 with TNF alpha (r = 0.89; P < 0.001), and IL-6 with TNF alpha (r = 0.89; P < 0.001). The mean levels of the three cytokines could not be compared because of the variations in the values. However, a trend toward lower levels in the three cytokines was noted in estrogen-treated women compared to the untreated postmenopausals. The bone-resorbing activity of monocyte supernatants, assessed by fetal long bone-resorbing assay, increased in untreated postmenopausal compared to that in premenopausal women (1.22 +/- 0.08 vs. 0.87 +/- 0.11; P < 0.05). In estrogen-treated patients, this activity decreased to premenopausal levels (0.89 +/- 0.04 vs. 0.87 +/- 0.11; P = NS). The resorbing activity was correlated to IL-1 (r = 0.28; P = 0.03), IL-6 (r = 0.52; P < 0.01), and TNF alpha (r = 0.48; P < 0.01). The addition of cytokine inhibitors and IL-1 receptor antagonist and TNF alpha antibodies to the supernatant bone culture medium induced a significant decrease in the calcium release. Those data show the involvement of several cytokines in the bone resorption process after estrogen deficiency.     

Impaired glucose tolerance, type 2 diabetes, and carotid wall thickness: the Insulin Resistance Atherosclerosis Study

OBJECTIVE: To assess whether people with impaired glucose tolerance (IGT) exhibit an increased risk of atherosclerosis as measured by the thickness of the carotid artery. RESEARCH DESIGN AND METHODS: We examined the relationship between glucose tolerance status and subclinical atherosclerosis in the Insulin Resistance Atherosclerosis Study (IRAS). The IRAS is an epidemiological study of 1,625 Hispanic, African-American, and white men and women, with approximately equal numbers of subjects with normal glucose tolerance (NGT), IGT, and type 2 diabetes as assessed by an oral glucose tolerance test. Half of those with diabetes were previously unaware of their condition and were defined as having new diabetes. Persons using insulin were excluded. The intima-media thickness (IMT) of the common carotid artery (CCA) and internal carotid artery (ICA) was measured as an index of subclinical atherosclerosis using B-mode ultrasonography. RESULTS: Adjusted for demographics and smoking, CCA-IMT increased most notably at the level of established diabetes (802, 822, 831, and 896 microm for NGT, IGT, new diabetes, and established diabetes, respectively). Adjustment for coronary heart disease (CHD) risk factors, which tended to worsen across glucose tolerance category, further minimized the slightly graded relationship. The relationship with the ICA-IMT was steeper and again suggested that the increased wall thickness is associated with diabetes, not with IGT. The relationship between glucose tolerance category and IMT was similar in men and women. CONCLUSIONS: We observed considerably greater IMT among persons with established diabetes but no significant increase in persons with IGT. These data suggest that the increased risk of CHD observed in persons with diabetes may largely develop after the onset of overt diabetes.     

Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993

Few studies have determined whether greater carotid artery intima-media thickness (IMT) in asymptomatic individuals is associated prospectively with increased risk of coronary heart disease (CHD). In the Atherosclerosis Risk in Communities Study, carotid IMT, an index of generalized atherosclerosis, was defined as the mean of IMT measurements at six sites of the carotid arteries using B-mode ultrasound. The authors assessed its relation to CHD incidence over 4-7 years of follow-up (1987-1993) in four US communities (Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland) from samples of 7,289 women and 5,552 men aged 45-64 years who were free of clinical CHD at baseline. There were 96 incident events for women and 194 for men. In sex-specific Cox proportional hazards models adjusted only for age, race, and center, the hazard rate ratio comparing extreme mean IMT (> or = 1 mm) to not extreme (< 1 mm) was 5.07 for women (95% confidence interval 3.08-8.36) and 1.85 for men (95% confidence interval 1.28-2.69). The relation was graded (monotonic), and models with cubic splines indicated significant nonlinearity. The strength of the association was reduced by including major CHD risk factors, but remained elevated at higher IMT. Up to 1 mm mean IMT, women had lower adjusted annual event rates than did men, but above 1 mm their event rate was closer to that of men. Thus, mean carotid IMT is a noninvasive predictor of future CHD incidence.     

Oral 17 beta-estradiol continuously combined with dydrogesterone lowers serum lipoprotein(a) concentrations in healthy postmenopausal women

Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis. Serum Lp(a) concentrations increase after menopause, and postmenopausal estrogen replacement appears to decrease Lp(a) levels. In a randomized, double blind study, we examined the effects of 6-month treatment with daily 17 beta-estradiol (E2; 2 mg, orally) continuously combined with one of four dosages [2.5 mg (n = 41), 5 mg (n = 38), 10 mg (n = 38), and 15 mg (n = 20)] of dydrogesterone on fasting serum Lp(a) concentrations in 137 healthy postmenopausal women. At baseline, no significant differences were noted among the four treatment groups. During the study period of 6 months the median serum Lp(a) concentration decreased significantly from 128 mg/L (range, 5-1660) to 110 mg/L (range, 1-1530) in the total population, corresponding to a reduction of 13% (P < 0.001). The percent changes in serum Lp(a) correlated positively with the percent changes in serum E2 at 3 as well as 6 months of therapy (r = 0.38; P < 0.001 and r = 0.35; P < 0.001, respectively). A dose response of dydrogesterone on serum Lp(a) was not found. In addition, serum lipids and (apo)lipoproteins improved significantly in all four treatment groups. In conclusion, oral E2 continuously combined with dydrogesterone has beneficial effects on the lipid and lipoprotein profile and is effective in lowering Lp(a) concentrations in postmenopausal women.     

Blood viscosity and elevated carotid intima-media thickness in men and women: the Edinburgh Artery Study

BACKGROUND: Several hemostatic and rheological factors have been associated with incident cardiovascular events. However, there have been no reports on the relationship of rheological factors with early atherosclerosis and very few on hemostatic factors. We therefore studied the relationship between these factors and carotid intima-media thickness (IMT). METHODS AND RESULTS: The Edinburgh Artery Study measured fibrinogen, tissue plasminogen activator (tPA), fibrin D-dimer, von Willebrand factor (vWF), blood and plasma viscosities, and hematocrit as part of its baseline examination during 1988-1989. At the 5-year follow-up, valid measurements of IMT had been recorded in 1106 men and women 60 to 80 years old. In men, blood viscosity (P< or =.001) and its major determinants, plasma viscosity, fibrinogen (both P< or =.01), and hematocrit (P< or =.05), were all linearly related to IMT. Furthermore, blood viscosity, fibrinogen (both P< or =.01), and plasma viscosity (P< or =.05) remained significantly associated on multivariate analysis. Correcting blood viscosity to a standard hematocrit of 45% had little effect on its association. In men, there was a significantly increased risk of having an IMT above versus below the upper quartile of its distribution (1.05 mm) for SD increases in blood viscosity (P< or =.01), fibrinogen, corrected blood viscosity, and plasma viscosity (all P< or =.05). With the exception of plasma viscosity, these risks were unaffected by adjustment for other common cardiovascular risk factors. No significant associations were found between any of the hemorheological factors and IMT in women or for tPA, fibrin D-dimer, or vWF in either sex. CONCLUSIONS: These findings suggest that in men, blood viscosity and its major determinants are associated not only with incident cardiovascular events but also with the early stages of atherosclerosis. This may be one explanation for the link between rheological factors and events.     

Rheology and filling characteristics of particulate dispersions in polymer melt formulations for liquid fill hard gelatin capsules

OBJECTIVE: In the postmenopausal years, women develop a central pattern of fat distribution and an increased risk of developing cardiovascular disease (CVD). The possibility that these events are related has not been extensively investigated. The object of the present study was to test the hypotheses that, 1) menopause-related differences in lipids are associated with greater estimated intra-abdominal adiposity, and 2) the relationship between individual adipose depots and plasma lipids differs with menopausal status. DESIGN: Cross-sectional. SUBJECTS: 141 healthy pre- and postmenopausal women aged 35-65 y. MEASUREMENTS: Total body fat by hydrodensitometry was used as an index of whole-body adiposity, the sum of five central skinfold measurements as an index of subcutaneous upper-body adiposity, and estimated intra-abdominal adipose tissue (IAF) as an index of visceral adiposity. Fasting plasma concentrations of total cholesterol (total-C), high- and low-density-lipoprotein cholesterol (HDL-C, LDL-C), and triglycerides were used as indices of CVD risk. RESULTS: Postmenopausal women had greater total body fat (P < 0.001), summed central skinfolds (P < 0.01), estimated IAF (P < 0.001), higher plasma concentrations of total-C (P < 0.001), LDL-C (P < 0.001) and triglycerides (P < 0.001), than premenopausal women. The relationship between central skinfolds and LDL-C differed with menopausal status, being significant in pre- but not postmenopausal women. Adjustment for estimated IAF with analysis of covariance decreased menopause-related differences in levels of total-C, LDL-C and triglycerides by approx 40-70%. CONCLUSION: These observations suggest that, 1) menopause-related changes in IAF may adversely affect the plasma lipid profile, and 2) menopausal status affects the relationship between central subcutaneous fat and LDL-C. Studies with measured IAF are needed to confirm present results.     

Relationship between spine bone mineral density and vertebral body heights

The aim of this study was to investigate the correlation between lumbar spine bone mineral density (LS-BMD) and the vertebral body heights with advancing age and years since menopause. One hundred and sixty-three women ages 39-74 years (77 normal premenopausal, ages 39-54, and 86 normal postmenopausal, ages 46-74 years) were studied. LS-BMD was measured by dual energy X-ray absorptiometry. Vertebral heights were evaluated, using morphometry, as the sum of anterior (AHs), middle (MHs), and posterior (PHs) vertebral body heights from T4 to L5. The AHs/PHs ratio at the same level was also calculated. AHs, MHs, PHs, and AHs/PHs ratio directly correlated with LS-BMD; the correlations are AHs r = 0.80, P < 0.0001, MHs r = 0.75, P < 0.0001, PHs r = 0.76, P < 0.0001, and AHs/PHs r = 0.66, P < 0.001. Both LS-BMD and AHs are inversely correlated with age, and the regressions fit with both linear and cubic curves. The statistical significance of the correlations persists while maintaining age constant. The linear regression curve of AHs with age indicates that the spine height decrement rate is 2.12 mm/year, corresponding to 7.4 cm in 35 years. AHs decreases immediately after menopause fitting with a cubic curve model, with a decrement rate of about 3 cm in the first 5 years after menopause. We conclude that the measurement of the sum of vertebral body heights could usefully integrate LS-BMD evaluation in the clinical and epidemiological investigation of osteoporosis.